New insight into why the heart doesn’t develop properly in some children

April 10, 2019
MUSC researcher Dr. Kyu-Ho Lee in his laboratory
Dr. Kyu-Ho Lee studies the genetics of the developing heart.

Almost one percent of all American babies are born with malformed hearts. Heart abnormalities are at once the most common and most deadly type of birth defect in the U.S.

Malformations of the right side of the heart have been linked to mutations in the master regulator gene Nkx2-5.

In a February 11 Scientific Reports article, a team of MUSC researchers led by Kyu-Ho Lee, M.D., Ph.D., assistant professor of pediatrics, report that Ccdc117, a target gene of Nkx2-5, produces a protein that supports the rapid growth of precursor cells. Such rapid growth is needed for proper development of right-sided heart structures.

“This is an unexpected finding that opens a new avenue for how we think about the genetic causes of congenital heart disease.”
-- Dr. Kyu-Ho Lee

The protein promotes cell growth by transferring iron-sulfur compounds from the mitochondria, where they are created, to the enzymes responsible for DNA replication and repair. Without the protein, the enzymes cannot make DNA or unwind it to make repairs. As a result, cell division stalls, limiting the number of heart precursor cells available for heart development.

“When we removed this protein, there was a substantial decrease in the rate of DNA synthesis and a very big increase in the amount of DNA damage,” explains Lee.

“The net result is that, without Ccdc117, cells stall in the early phases of division.”

Nkx2-5 has long been thought to promote the growth and division of precursor heart cells. However, before the finding by Lee’s team, researchers did not know how it did so.

“Cell division is an important issue in the developing heart,” explains Lee.

“We proved that there's a linkage between Nkx2-5, a gene that's very well known to be a frequent cause of congenital heart disease, and this iron metabolism pathway, which is also well known to control cell division.”

Mitochondria, which assemble iron-sulfur compounds, were once thought of simply as the powerhouse of the cell. They are now known to play important roles in many biological functions, including DNA repair and replication.

This linkage between Nkx2-5 and the iron metabolism pathway leads Lee to wonder whether lifestyle modifications by the pregnant mother, such as increased exercise and improved nutrition, could lessen the likelihood of heart malformations in the fetus.

Exercise can increase the number of mitochondria, thereby increasing the assembly of iron-sulfur compounds needed for improved DNA repair and replication.

“This is an unexpected finding that opens a new avenue for how we think about the genetic causes of congenital heart disease,” says Lee.

“For the first time, it implicates a pathway involving iron metabolism. It provides a link between programs that control heart development that we know go wrong in congenital heart disease and everyday cell function that can be affected by things like nutrition and exercise and metabolism.”

For now, any connection between the general health of the mother and the risk of heart malformation in the fetus remains speculative. A definitive answer will require further study.

In future studies, Lee plans to examine the biochemistry underlying this pathway and to identify the types of congenital heart disease to which it is relevant.

“Our findings offer a new way of thinking about cell mechanisms that relate to congenital heart disease,” says Lee.

“Iron-sulfur clusters have been in the background for decades in research into mitochondria. We are now beginning to understand their broader implications for general cell function. Our work once again underlines the significance of this pathway.”

Lee is also currently studying whether the expression of Ccdc117 in placental tissue plays a role in the growth of cells that knit together the maternal and fetal circulation. He is exploring whether its absence or underexpression is linked to preeclampsia, a hypertensive disorder of pregnancy that threatens mother and baby alike.

Ccdc117 is a crossover gene of interest in the two lines of his research. Lee’s studies of this crossover gene were supported by pilot project funding from the South Carolina Clinical & Translational Research Institute, an NIH-funded Clinical and Translational Science Awards hub.

About the Author

Kimberly McGhee

Keywords: Pediatrics, Heart Stories, Research